This tiny brain parasite seems to make rodents braver—and it likes humans, too

Confusion between fear and sex

In addition to making rats less scared of cat urine, Vyas found that Toxo infection changed the way that rats interacted with each other. It made male rats more attractive to females. That’s actually quite unusual—females of many species typically avoid parasite-infected males. He also found a potential reason for Toxo to have evolved this behavioral effect: the parasite was sexually transmittable in rats. “I think it will be very difficult to come up with two separate mechanisms for these two behavioral changes, so we’re taking the view that these are both two sides of the same coin,” Vyas said.

Vyas’s current hypothesis is that the behavioral effects aren’t due to the parasite going to brain, but rather to its presence in another site where it forms cysts: the testes. Toxoplasma infection increases testosterone synthesis in male rats, and Vyas suggests that this increased testosterone mediates the production of pheromones that make males more attractive to females, as well as making changes in their brains that make them less scared of cats. “The beautiful thing about this system is that it explains both behavioral changes,” Vyas said.

Vyas’s results suggest that the Toxo-induced increase in testosterone causes epigenetic changes in a specific part of the brain that processes odor and pheromone information, which shifts the rat from wanting to hide or escape to wanting to breed. Artificially inducing similar epigenetic changes made rats less afraid of cats, even without a Toxo infection. Conversely, blocking such epigenetic changes in rats or castrating them so they couldn’t produce testosterone also blocked Toxo’s effects on the rats’ fearful response to cat urine.

Vyas also looked at neurons in this brain region (the medial amygdala) that were normally recruited by things that would make the rats want to breed, such as the presence of female rats. When male rats were infected with Toxo, these neurons were now being recruited by cat odors, a stimulus that should make them scared rather than horny. “In other words, there is a mix-up between defensive and reproductive behavior,” said Vyas. “The parasite then is just tapping into a pre-existing circuit.”

It’s an intriguing hypothesis, but it’s still preliminary and the studies need replication. Plus, there are still some loose ends to tie up—for instance, how would this mechanism work in females? Female rats show similar responses to cat urine as males when infected with Toxo, but they produce much less testosterone and have fewer of the neurons that are recruited by cat odors. Vyas is still trying to figure out whether the same testosterone-based mechanism that he posits in males would also work in females, or whether they have their own parallel circuit. Regardless, the findings do suggest a way that Toxo could cause its behavioral effects without needing to be in the brain.

Researchers are also considering the possibility that Toxo does need to be in the brain to have its effects, but the effects are indirect. “What we do know with Toxo is that it does elicit a very strong inflammatory immune response, it does get into the brain, and so the inflammatory response occurs in the brain itself, which is not a site that most microbes can get to,” said Vern Carruthers, a parasitologist at the University of Michigan. There’s an established link between immune response and behavior in the literature, an effect that’s been seen in rodents.

The idea that Toxo’s behavioral effects involve the immune system isn’t new. But Ingram’s work showed that all three Toxo strains, even the mutated one that didn’t form brain cysts, elicited a brief inflammatory response in the brain. It’s possible that this immune response makes some lasting changes to the brain, leading to a change in behavior, though a lot more work need to be done here.

If Toxo’s effects are due to the host’s immune response to it, then the parasite doesn’t have to do anything special to change the way its victims act. That raises a more basic question: does Toxo actively manipulate its host?

Enlarge/ This is a scanning electron micrograph of the protozoan parasite Toxoplasma gondii, tissue cyst in brain of an infected mouse.

The parasite or the host?

We know Toxo infection causes behavioral effects. But is the parasite a devious puppetmaster, manipulating its host’s behavior to increase its transmission into cats? The behavioral manipulation hypothesis assumes that by making rodents lose their fear of cats, Toxo increases its transmission to its feline host. It’s a perfectly reasonable suggestion, but it turns out this idea is quite hard to demonstrate.

“There is no hard data either for or against the idea that behavioral changes increase transmission to cats,” said Amanda Kristancic, a zoologist at Murdoch University in Australia. Another parasite related to Toxo, Eimeria vermiformis , appears to similarly make mice less scared of cats. But unlike Toxo, this parasite doesn’t rely on cats for transmission—in fact, if cats kill the Eimeria -infected mice, the parasite would die, too. As a result, Eimeria researchers have no reason to think that the parasite causes this behavior or benefits from it, Kristancic said.

Both Nanyang Technological University’s Vyas and Geisinger Health System’s Ingram agreed that it would be important to confirm if the loss of fear caused by Toxo infection actually results in increased rodent predation. But again, that’s a hard experiment to do. “The perfect experiment would be release half mice that are infected, half mice that aren’t, in a barn that’s enclosed, and then let a couple of cats out, and catch all the mice at the end and figure out how many got eaten and which ones,” said Ingram. “But no one’s going to let you do that, it’s horrible.”

Researchers could also study Toxoplasma transmission by conducting more predation studies in the wild and in other animals. A recent study found that wild chimpanzees infected by Toxoplasma had a similar loss of aversion to the smell of leopard urine. There were only nine infected chimpanzees, and the study was correlative, so one can’t read too much into it. But it does at least open up the possibility that the loss of fear of feline predators occurs in species beyond mice and rats. Follow-up studies looking at Toxo’s effects in birds might be particularly interesting, as they’re also a prey species of cats.

What of Toxo’s effects in humans, such as its association with schizophrenia or suicide attempts? They may not require active manipulation by the parasite either. One idea is that, as in rodents, they may be the result of our body’s immune response to Toxo. For reasons that have nothing to do with this parasite, some researchers have suggested that immune and infectious causes might be responsible for a range of human behavioral effects and neurological disorders, including Alzheimer’s disease, schizophrenia, and autism. For now, it’s a hotly-debated topic. “It’s been known for a while that there are changes in the inflammatory status of the brain in people with schizophrenia,” said Carruthers. “What’s unknown is whether it’s playing a causal role or it’s just a consequence.” Similar things could be said about the other disorders.

So when it comes to humans, it turns out it can be quite hard to pin down exactly what Toxo does, let alone how it does it.

A hard thing to study

Toxoplasma infects a lot of us—almost a quarter of Americans, a third of all humans worldwide, and more than 90 percent of the population in some countries. We get it mostly from undercooked meat, or from handling cat litter or contaminated soil. Thankfully, as long as you’re healthy, it just feels just like a mild flu, although it can have more severe consequences if you’re pregnant or have a weakened immune system.

Enlarge/ An image of GFP+ neurons, 1 is infected with a cyst (red) and one is not.

Carla Cabral, Koshy Lab, University of Arizona

Toxo infection has also long been associated with a number of behavioral and neurological effects in humans. “ Evidence is strongest for schizophrenia, but also quite strong for affective disorders in general, and especially suicide attempts,” said Fuller Torrey, a psychiatrist at the Stanley Medical Research Institute. How does a loss of fear of cats translate to all these different effects in humans? “Very few of us are likely to be eaten by large cats, so Toxoplasma gondii doesn’t accomplish anything by getting in us, but it doesn’t know it’s in a dead-end host, it just kind of does its thing,” said Torrey. “It’s smart, but it’s not that smart.”

In interpreting the human studies, it doesn’t help that there’s still a distinct lack of scientific consensus about what effects Toxo actually has. “I still take lot of human studies with quite a bit of salt,” Nanyang Technological University’s Vyas said. “I’m not saying that the experiments are not good, but that the interpretation is fraught with a lot of complications.” Many researchers Ars spoke to pointed out that Toxo infection rates vary dramatically around the world, from a few percent of the population to more than 90 percent in some countries, whereas rates of schizophrenia are fairly constant around the world at 0.5-1 percent.

The reality is that human behavior and mental illness are complex, and many of the Toxo studies are not standardized and have yet to be replicated. Toxo certainly doesn’t make it easy to do this work—there’s no good way to detect Toxo cysts in a living person, and the studies rely on correlations with Toxo antibody levels. But antibodies are a crude measure that don’t tell you about a number of things that could affect behavior, such as when the infection occurred or which strain of the parasite you’re infected with.

To get at causation, larger studies that track people from a young age could help figure out if their behavioral symptoms show up before or after Toxo infection. Another approach would be to get rid of the parasite from an infected person who has a mental illness, and see if their clinical symptoms improve. But Toxo doesn’t let us do that yet—we currently don’t have a good way to get rid of Toxoplasma cysts once a person is infected.

The bottom-line? Toxo remains intriguing but complicated. “If there was some huge major behavioral differences, then we would have seen it by now,” said Zi Teng Wang, a parasitologist at Washington University in St. Louis. “It could be having some effect, but I wouldn’t worry about brain parasites making me crazy anytime soon.”

Sandeep Ravindran is a freelance science journalist based in New York City. He has written about life sciences and technology for publications such as Smithsonian, National Geographic News, The Verge, Popular Science, and Backchannel. His other work is posted on Twitter @sandeeprtweets and at sandeepr.contently.com.